Disposable medical devices have been widely accepted from the standpoint of the prevention of hospital infection and medical economy, and many improvements have been added thereto. For instance, there have been in practical use those devices, used by insertion in to a living body, having a hydrophilic coating, which is provided on the surface of a medical device, is swollen with a body fluid or a physiological saline solution and shows lubricity. The role of the hydrophilic coating is to reduce frictional resistance with the tissues of the living body wherein the frictional resistance with the living body tissues is reduced through the lubricious surface. As a consequence, easy operations of insertion, rotation and back-and-forth movements of medical devices are ensured and such a coating is very useful in shortening the amount of procedural time and mitigating the patient's pain associated with insertion and removal.
Disposable medical devices, as a sterilized product, have been manufactured and commercially sold from pure-play companies and provided to medical institutions. Among them, most catheters are made up of synthetic polymer materials, for which ethylene oxide gas (EOG) sterilization has been adapted. In other words, for existing hydrophilic polymer-coated catheters or guide wires, EOG sterilization has been predominantly adopted in view of the concerns of material degradation and functional lowering as a product.
In recent years, there have been demanded sterilization methods using no EOG, which is a specified chemical substance (toxic substance), in consideration of environmental problems. Hence, radiation sterilizations using radiations such as a γ-ray, X-ray, electron beam (EB) and the like have been reviewed. The initial process of damaging activity (bactericidal activity or bacteriostatic activity) against microorganisms is ascribed to the reaction between an activated molecular species having high chemical reactivity, such as an ion, radical or the like, which is generated through interaction between a radiation and a constituent molecule of an organism or a molecule in the vicinity thereof, and DNA of the microorganism or other type of biomolecule. The activated molecular species is generated on the basis that with γ-ray and X-ray irradiations, high-speed electrons ejected from a substance by the action of the γ-ray further cause the substance to be ionized or excited in most cases. With electron beam irradiation, high-speed electrons are directly injected into a substance, meaning that the electron beam and g-ray and X-ray substantially have the same functional mechanism.
Taking it into consideration that when making use of normal temperature treatment and radiotransparency that are characteristic of radiation sterilization, a radiation can be irradiated from outside after packaging thereby enabling the treatment to the center, the high penetrating power of γ-rays has been a great merit. However, the performance of electron accelerators has been improved in the 1990's and thus, satisfactory permeability could be obtained, for which electron beam radiation to medical devices has been attempted and such electron beam (EB) sterilization has steadily increased in number from the latter part of the 1990's.
Where radiation sterilization is applied to medical devices that have been hitherto subjected to EOG sterilization, it is necessary to check the degradation and durability of materials and products after the radiation sterilization of intended medical devices. More particularly, it is of necessity to check mechanical characteristic changes, an unusual odor and coloration formed, and the presence or absence of elution of decomposed products after irradiation. The details thereof, especially with respect to a method of confirming merchantability in radiation sterilization, are set forth in International Standard ISO 11137.
The inventors of the present invention have engaged in application and investigation of radiation sterilization of medical devices and experienced a variety of problems involved in the investigation of electron beam sterilization applied to products that have been hitherto sterilized with EOG. Especially, as to hydrophilic polymer-coated medical devices in more detail with respect to the elution resistance and sliding performance of hydrophilic polymer-coated catheter/guide wire, we have experienced some instances where an increase in amount of an eluted matter and functional degradation (a lowering of sliding performance or lowering of lubricity) under specified conditions are more likely to occur in electron beam sterilization when comparing with EOG sterilization.
It is known that the membranes used in blood treating devices (a kidney dialysis device, a dialyzer) suffer a damage by radiation irradiation and degrade thereby increasing an amount of an eluted matter from a hollow fiber membrane. Many attempts have been proposed up to now for material degradation at the time of radiation sterilization, particularly with respect to the problem on the increased amount of an eluted matter. For instance, in Patent Document 1 and Patent Document 2, there is disclosed a sterilization method wherein when dialyzer products in a dried condition are sterilized, a deoxidant is incorporated along with a humidity controlling agent, if desired, so as to carry out sterilization substantially under oxygen-free conditions. In Patent Document 3, there is disclosed a sterilization method wherein sterilization is performed substantially under oxygen-free conditions after hermetic sealing in a gas impermeable material container along with a moisture-releasing deoxidant.
These sterilization methods are performed substantially under oxygen-free conditions and thus, cannot make use of oxygen molecular species, especially, oxygen radicals or ozone, which have strong damaging activity against microorganisms. This invites an increase in sterilization dose so as to enhance a bactericidal effect, with the attendant problem that material degradation is caused owing to the high dose. Moreover, there is concern that in the absence of oxygen, there arises a problem of proliferation of anaerobic bacteria, especially obligate anaerobes.
In order to suppress material degradation, there is disclosed, for example, in Patent Document 4, a method wherein a sterilization-protecting agent (glycerine, polyethylene glycol or the like) is contained in a hollow fiber membrane and a γ-ray is irradiated under conditions of a moisture content of not greater than 30%. However, the use of the sterilization-protecting agent is inconvenient in that sterilization-protecting agents that have never been employed for existing EOG sterilization are required, leading to cost rises. In addition, it is not favorable from the standpoint of safety and development of lubricity that sterilization-protecting agents such as glycerine, etc., are coated and left on hydrophilically-coated catheters or guide wires.
In Patent Document 5, there is disclosed an irradiation sterilization method of a blood treating device, which is characterized in that a hollow fiber membrane made of a polysulfone resin and a hydrophilic resin is sterilized by irradiation under conditions of a moisture content of not higher than 5% and a relative humidity of not higher than 40% in the atmosphere around the hollow fiber membrane.
On the other hand, as described in Patent Document 6, there is known a method of preventing a hollow fiber membrane from degrading wherein when a γ-ray sterilization is carried out, the hollow fiber membrane becomes wetted to a level not lower than a water saturation content.
By the way, when comparing Patent Document 5 and Patent Document 6 with each other, a difference in moisture content is recognized. It is considered that in the instance of Patent Document 5, this is achieved for the first time by combination of a polysulfone membrane and a hydrophilic resin. Accordingly, a difficulty is involved in applying, as it is, to hydrophilic polymer-coated catheters and guide wires making use of a variety of materials. The method of subjecting a hollow fiber membrane disclosed in Patent Document 5 to wetted conditions of not lower than a water saturation content or the sterilization method of a water-filled dialyzer are not favorable from the standpoint of transport cost rises based on the increase in weight of product and proliferation of microorganisms during transport and storage, and have never been put into practice.
Besides, in Patent Document 7, there is disclosed a high-performance hollow fiber membrane-type blood purifying device, which is characterized in that a radical spin content in the hollow fiber membrane after radiation sterilization is at not greater than 20.0×1016 spins/g. In this case, the material is limited to a polysulfone film. Limitation is also placed on the case where a polysulfone-based, hollow fiber-type blood treating device is hermetically sealed, along with a deoxidant, in a container made of a gas impermeable material, under which sterilization is carried out by irradiation of a gamma ray. A difficulty is involved in applying, as it is, such a conventional technology for the radiation sterilization method of a dialyzer achieved by limiting the type of material to catheters or guide wires to which EOG sterilization has been applied up to now.
In Patent Document 8, there is disclosed, as a method of preparing a hydrophilic polymer-coated catheter, a sterilization method wherein radiation irradiation is performed during the course of wetting with a polyvinylpyrrolidone (PVP) solution. In this method, it is meant to coat the uppermost surface with crosslinked PVP. Thus, this method cannot be applied to other types of hydrophilic polymer products because polymer coating agent-derived lubricity inherently belonging to the product is changed. To use, as it is, the PVP solution containing an organic solvent upon final sterilization has concerns about safety of the residual organic solvent on a living body.
In Patent Document 9, there are disclosed, as an application of a medical hydrogel made up of different types of polymer compounds, a method wherein a solution containing a polymer of high biocompatibility and a radiation crosslinking polymer compound is coated onto a body of a medical device and subjected to radiation irradiation to fix on the surface of the medical device body, and also a method of making the medical device. In this literature, a hydrophilic polymer-coated guide wire is exemplified as a medical device and it is indicated that film formation by radiation crosslinking is possible. However, no mention is made of the lubricating performance of the guide wire, and no mention or suggestion is made of whether or not radiation sterilization is applicable to guide wires.
More particularly, the radiation sterilization technique that has been hitherto studied mainly to cope with the problem of an eluted matter from the polysulfone film of a dialyzer cannot be applied, as it is, to catheters or guide wires having been subjected to hydrophilic polymer coating. In addition, there has never been reported any technique or knowledge relating to an eluted matter and the stabilization of sliding performance in case where radiation sterilization is applied to catheters or guide wires coated with a hydrophilic polymer.